US11369653B2 - Traditional Chinese medicine composition for treating cardiovascular and cerebrovascular disease, preparation method therefor and use thereof - Google Patents

Traditional Chinese medicine composition for treating cardiovascular and cerebrovascular disease, preparation method therefor and use thereof Download PDF

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US11369653B2
US11369653B2 US17/048,438 US201817048438A US11369653B2 US 11369653 B2 US11369653 B2 US 11369653B2 US 201817048438 A US201817048438 A US 201817048438A US 11369653 B2 US11369653 B2 US 11369653B2
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Hongzhang Jia
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/236—Ligusticum (licorice-root)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/21—Amaranthaceae (Amaranth family), e.g. pigweed, rockwort or globe amaranth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/46—Eucommiaceae (Eucommia family), e.g. hardy rubber tree
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8962—Allium, e.g. garden onion, leek, garlic or chives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying

Definitions

  • the present disclosure belongs to the field of drug research and development, and in particular the present disclosure relates to a Traditional Chinese Medicine composition for treatment of cardiovascular or cerebrovascular diseases and its preparation method.
  • Cardiovascular and cerebrovascular diseases represent a serious threat to human health, especially the elderly over 50 years old.
  • the diseases are characterized by high morbidity, high disability and high mortality.
  • incidence rate and mortality rate of cardiovascular and cerebrovascular diseases are increasing in both rural and urban areas in recent fifty years.
  • cardiovascular and cerebrovascular diseases are the first cause of death due to diseases in China.
  • Cardiovascular and cerebrovascular diseases are also the main cause of death in western countries.
  • Coronary heart disease the full name of which is coronary atherosclerotic heart disease, sometimes also known as ischemic heart disease or coronary disease, refers to the heart disease caused by myocardial ischemia and hypoxia due to coronary atherosclerosis.
  • Coronary artery is the only blood vessel that supplies blood to the heart, and as its shape is like a crown, it is called coronary artery. This blood vessel will also become sclerotic along with the whole body blood vessels, showing an atherosclerotic change, causing cardiovascular blood circulation disorders and resulting in myocardial ischemia and hypoxia, namely coronary heart disease.
  • CHD is a common and frequently occurring disease in middle-aged and elderly people, which seriously endangers people's lives.
  • CHD can be divided into five types: occult type, angina pectoris, myocardial infarction, arrhythmia and sudden death.
  • Heart failure refers to the cardiac circulation disorder syndrome, the symptoms of which are mainly pulmonary congestion and vena cava congestion, wherein the venous return blood cannot be fully discharged from the heart due to systolic and/or diastolic dysfunction of the heart, resulting in blood stasis in the venous system and insufficient blood perfusion in the arterial system.
  • Heart failure is usually not an independent disease, but the terminal stage of the development of some heart diseases.
  • Clinically, heart failure can be manifested as acute heart failure and chronic heart failure.
  • heart failure can be divided into systolic or diastolic heart failure
  • cardiovascular and cerebrovascular diseases such as coronary heart disease, heart failure, etc.
  • myocardial diastolic dysfunction are urgently needed.
  • TCM Traditional Chinese Medicine
  • Coronary heart disease and heart failure are often diagnosed as chest obstruction in traditional Chinese medicine.
  • chest obstruction is a kind of disease characterized by chest tightness, chest pain (or even penetrating to the back) and shortness of breath.
  • TCM diagnosis and treatment of chest obstruction can be divided into five types: heart blood stasis type, phlegm turbidity and blood stasis cold type, Yin cold stagnation type, heart and kidney Yin deficiency type, Qi and Yin deficiency type.
  • An object of the present disclosure is to provide a novel Chinese medicine composition for the treatment and/or prevention of cardiovascular or cerebrovascular diseases (such as coronary heart disease, heart failure, angina pectoris, myocardial infarction, thrombosis, stroke, etc.).
  • cardiovascular or cerebrovascular diseases such as coronary heart disease, heart failure, angina pectoris, myocardial infarction, thrombosis, stroke, etc.
  • Another object of the present disclosure is to provide a novel Chinese medicine combination for treating and/or preventing cardiovascular or cerebrovascular diseases caused by myocardial systolic dysfunction, myocardial diastolic dysfunction, thrombosis, myocardial ischemia, myocardial hypoxia, or myocardial fatigue, especially myocardial diastolic dysfunction.
  • the present disclosure provides a traditional Chinese medicine composition for the treatment of a cardiovascular or cerebrovascular disease, and the active ingredients thereof are composed of the following components 1) and 2):
  • the extracts of Rhizoma Chuanxiong, Radix Curcumae and Radix Cyathulae are used as the active ingredients. It is understood by those skilled in the art that the traditional Chinese medicine composition can also comprise other auxiliary medicinal materials or excipients (such as auxiliaries, adjuvants or drug excipients, etc.) as required.
  • the traditional Chinese medicine composition may be consisting of the above component 1) and component 2).
  • the traditional Chinese medicine composition may further contain other auxiliary medicinal materials or excipients.
  • a traditional Chinese medicine composition for the treatment of a cardiovascular or cerebrovascular disease is composed of the following components 1), 2) and 3):
  • the present disclosure provides a method for preparing a traditional Chinese medicine composition, comprising the following steps:
  • step (3) combining the concentrates of step (1) and step (2) and then drying.
  • the traditional Chinese medicine composition disclosed herein can be formulated into various pharmaceutically acceptable oral dosage forms (such as tablets, capsules, granules, pills, oral liquid, etc.) as needed, which comprise the traditional Chinese medicine composition disclosed herein and a conventional medicinal adjuvant or auxiliary material.
  • the traditional Chinese medicine composition disclosed herein can also be formulated into various forms of oral health care products as needed, which comprise the traditional Chinese medicine composition disclosed herein and a conventional adjuvant or auxiliary material.
  • the traditional Chinese medicine composition disclosed herein can be used to treat or prevent cardiovascular or cerebrovascular diseases, especially coronary heart disease, heart failure (including systolic heart failure or diastolic heart failure), angina pectoris, myocardial infarction, thrombosis and stroke.
  • cardiovascular or cerebrovascular diseases especially coronary heart disease, heart failure (including systolic heart failure or diastolic heart failure), angina pectoris, myocardial infarction, thrombosis and stroke.
  • the traditional Chinese medicine composition disclosed herein is particularly suitable for treating and/or preventing myocardial systolic dysfunction, myocardial diastolic dysfunction, thrombosis, myocardial ischemia, myocardial hypoxia, or myocardial fatigue, or cardiovascular and cerebrovascular diseases caused by these diseases, especially myocardial diastolic dysfunction or cardiovascular and cerebrovascular diseases caused by myocardial diastolic dysfunction.
  • the present disclosure provides a method for treating or preventing a cardiovascular or cerebrovascular disease, in particular, such as coronary heart disease, heart failure (including systolic or diastolic heart failure), angina pectoris, myocardial infarction, thrombosis, and stroke, comprising administering a therapeutic effective amount of the Chinese medicine composition disclosed herein to a patient.
  • a cardiovascular or cerebrovascular disease in particular, such as coronary heart disease, heart failure (including systolic or diastolic heart failure), angina pectoris, myocardial infarction, thrombosis, and stroke, comprising administering a therapeutic effective amount of the Chinese medicine composition disclosed herein to a patient.
  • the medical composition as prepared may have at least one of the following advantages:
  • the disclosure provides a compound preparation, which is mainly used for the treatment of chest obstruction (diagnosed as coronary heart disease by modern medicine) and has been developed based on TCM theory about Qi stagnation and blood stasis combined with modern medical theory about myocardial systolic and diastolic dysfunction function.
  • chest obstruction and heart pain are mainly caused by obstruction of heart Qi and blood circulation.
  • coronary heart disease is mainly caused by imbalance between coronary blood flow and myocardial demand. They are highly consistent in this regard.
  • the etiology of chest obstruction is deficiency of vital energy in the body, invasion of external pathogenic factors, improper diet, excessive emotions, maladjustment of work and rest, etc., resulting in blockage of pulse and imbalance of Yin and Yang in the heart, Qi and blood.
  • the disease is mainly manifested by suffocation and pain in the chest, and is considered to be equivalent to coronary heart disease or angina pectoris diagnosed by modern medicine.
  • chest obstruction and heartache which are attributed to Qi stagnation and blood stasis and the symptoms of which are chest pain, chest tightness, palpitation, dark tongue or ecchymosis on tongue, and astringent or stringy pulse.
  • the pathogenesis of chest obstruction and heartache is Qi stagnation and blood stasis.
  • the disease is often caused by excessive emotions and abnormal emotions, which damage viscera, and the deficiency in viscera function leads to the loss of regulation of Qi and blood and in turn causes Qi stagnation and blood stasis, or caused by improper diet, such as overeating fat and sweet food, alcoholism and overeating raw and cold food, which causes injury to the spleen and stomach, promotes generation of phlegm and dampness-evil, and in turn leads to Qi stagnation and blood stasis due to the inhibition of Qi and blood circulation by dampness-evil; or caused by maladjustment of work and rest, wherein overwork consumes Qi and injures Yin, and excessive relaxation leads to stagnation of Qi and blood circulation, resulting in Qi stagnation and blood stasis.
  • the main treatment methods are promoting Qi movement and activating blood circulation, dredging meridians and collaterals, and relieving pain.
  • the treatment should mainly aim at regulating the relationship between Qi and blood as well as the functional disorder and imbalance. Because “Qi flows then blood flows”, the treatment of blood stasis should focus on regulation of Qi, and Qi moves smoothly when blood stasis is resolved. According to the “Theory of Blood Syndrome and Viscera Pathogenesis”, “if Qi is flushed and regulated, the blood vessels will become smooth”. If Qi and blood are regulated smoothly and blood vessels are unobstructed, the stasis disease will be eliminated. Therefore, promoting Qi movement, activating blood circulation and relieving pain are a kind of method for treating both root causes and symptoms.
  • the present disclosure provides a traditional Chinese medicine composition for the treatment of a cardiovascular or cerebrovascular disease, and the active ingredients are composed of the following components 1) and 2):
  • Rhizoma Chuanxiong, Radix Curcumae and Radix Cyathulae are used as the active ingredients of the traditional Chinese medicine composition. These three medicines can be used alone, or in combination with other auxiliary herbs, such as 5-10 parts of Bulbus Allii Macrostemonis and 6-12 parts of Cortex Eucommiae, which are used to assist in the treatment of complications caused by coronary heart disease and heart failure, such as shoulder and back pain.
  • Radix Curcumae pungent, bitter, cool, acting on heart meridian, lung meridian and liver meridian. It can be used as a Monarch medicine and can cool blood and break blood stasis. According to the “ Compendium of Materia Medica ”, it can “act on the heart and wrapping meridian” and can be used for “treating blood Qi and treating heart and abdominal pain”.
  • Rhizoma Chuanxiong also known as Ligusticum wallichii : pungent, warm, acting on liver, gallbladder and pericardial meridian. It can promote blood circulation and Qi movement. It can be used as a Minister medicine to relieve pain. The combination of the Monarch medicine and Minister medicine can strengthen the efficacy promoting blood circulation and Qi movement. Both of them act on the heart meridian or pericardium meridian, promote blood circulation and Qi movement, and provide benefits to the heart pulse.
  • Radix Cyathulae sweet, slightly bitter, mild, acting on liver and kidney meridian. It is used as an Assistant medicine in the five-medicine formulation and as a Minister medicine in the three-medicine formulation to remove blood stasis and dredge collaterals. It can activate blood circulation and remove blood stasis, and has the function of dredging collaterals. According to the book of “Materia Medica Jing Shu”, “it is beneficial to descending, . . . and it can expel Qi and blood, especially resolve Qi stagnation and blood coagulation”.
  • Radix Curcumae can induce Qi in heart, lung and liver, Rhizoma Chuanxiong can guide Qi and blood to go up, and Radix Cyathulae can guide Qi and blood to go down. So, the combination of the three medicines (or five medicines) disclosed herein can make Qi and blood circulate around the body. Therefore, the movement of Qi and circulation of blood is promoted, blood stasis is removed, and pain is relieved. Radix Curcumae has slightly different pharmaceutical properties due to different places of production, wherein. Curcuma Wenyujin or Radix Curcuma Kwangsiensis are preferably used.
  • Bulbus Allii Macrostemonis also known as Allium macrostemon : pungent, bitter and warm, acting on heart, lung, stomach and large intestine meridian. It can dredge Yang and disperse coagulation. It can be used as an Assistant medicine to help movement of Qi and remove stagnation. In the compositions, it helps the Monarch and Minister to dispel the chest obstruction, heartache and abdominal distension. According to “Ben Cao Qiu Zhen”, it can “promote the flow of Qi, lubricate orifices, and help Yang”.
  • Cortex Eucommiae also known as Eucommia ulmoides
  • It can tonify liver and kidney is beneficial to kidney Yang and heart Yang, and helps to keep the circulation of Qi and blood smooth. It is used to assist the Monarch and Minister to treat the pain of shoulder and back.
  • Chinese patent application CN103933474A discloses a pharmaceutical composition for the treatment of coronary heart disease, which is a prepared from raw materials with the following weight ratios: 15-20 parts of Salvia miltiorrhiza, 10-15 parts of Angelica sinensis, 10-15 parts of unprocessed Radix rehmanniae, 10-15 parts of Radix rehmanniae preparata, 10-15 parts of Paeoniae rubra, 10-15 parts of Semen persicae, 7-11 parts of Flos carthami, 4-8 parts of Rhizoma Chuanxiong, 8-12 parts of Cyperus rotundus, 8-12 parts of Radix Curcumae, 8-12 parts of Radix bupleuri, 8-12 parts of Radix Paeoniae Alba, 4-8 parts of Radix platycodonis, 8-12 parts of Radix Cyathul
  • the composition of CN103933474A contains four kinds of Qi regulating and detoxifying medicines including Cyperus rotundus, Radix bupleuri, Radix platycodonis and Radix glycyrrhizae , five kinds of blood activating drugs including Salvia miltiorrhiza, Semen persicae, Flos carthami , Rhizoma Chuanxiong and Radix Cyathulae, and five blood tonic drugs including Angelica sinensis , unprocessed Radix rehmanniae, Radix rehmanniae preparata and Paeoniae rubra , and thus is used to replenish Qi and tonify blood, and its main indication is blood deficiency syndrome (mostly seen in middle-aged and elderly people).
  • composition disclosed herein is composed of Rhizoma Chuanxiong, Radix Cyathulae and Radix Curcumae (or further supplemented with Bulbus Allii Macrostemonis and Cortex Eucommiae), and its main indication is chest obstruction and heartache caused by Qi stagnation and blood stasis (mainly caused by excessive emotions or abnormal emotions, and seen in all age groups). Therefore, the two kinds of compositions are significantly different in formulation, pharmacology, efficacy and indication.
  • Rhizoma Chuanxiong, Radix Cyathulae and Radix Curcumae account for a very small portion of the composition, and thus should not be considered as the main active ingredients of the composition.
  • specific extracts of Rhizoma Chuanxiong, Radix Cyathulae and Radix Curcumae are used as the active ingredients of the composition disclosed herein.
  • composition of CN103933474A can be extracted with water or ethanol; while the traditional Chinese medicine composition disclosed herein cannot be obtained by simply mixing the raw materials and directly extracting them with water or ethanol, but can only be obtained by using a specific combination of extracts. Therefore, the active ingredients of the two compositions are obviously different at the molecular level.
  • the inventor has demonstrated that the traditional Chinese medicine composition (including three-medicine formulation and the five-medicine formulation) has significant therapeutic effect on myocardial systolic and diastolic disorders, platelet aggregation and thrombosis, myocardial ischemia, hypoxia, myocardial fatigue, etc., and is safe and reliable, and has no toxic side effects on human body. Specifically, the following effects have been observed.
  • the raw materials for the composition disclosed herein are all are commonly used herbs, and are described in detail in “Chinese Pharmacopoeia” and/or “Chinese Materia Medica”, and can be easily obtained commercially.
  • ethanol may refer to either absolute ethanol or an ethanol solution in water, for example 40-95% ethanol solution in water or 40-80% ethanol solution in water, preferably 50-70% ethanol solution in water.
  • ethanol aqueous solutions of various concentrations such as 60%, 65%, 70%, etc., can be used. The above concentration refers to the volume concentration.
  • a herbal raw material or component referred to as “optional” in the present disclosure may be included in some embodiments while absent in other embodiments.
  • steps or processes referred to “optional” may be included in some embodiments while absent in other embodiments.
  • the amount of each medicine provided in the disclosure generally refers to its weight unless otherwise specified. It can be understood by those skilled in the art that a certain error is allowed for the amount specified herein, and the error is usually within the range of ⁇ 8%, ⁇ 5% or ⁇ 3%.
  • the preferred relative amount of each raw medicine used in the composition is as follows:
  • Rhizoma Chuanxiong preferably 6-12 parts, more preferably 8-10 parts, and most preferably about 9 parts;
  • Radix Curcumae preferably 5-10 parts, more preferably 6-8 parts, and most preferably about 7 parts;
  • Radix Cyathulae Curcumae: preferably 5-10 parts, more preferably 6-8 parts, and most preferably about 7 parts.
  • Bulbus Allii Macrostemonis preferably 5-10 parts, more preferably 6-8 parts, and most preferably about 7 parts;
  • Cortex Eucommiae preferably 6-12 parts, more preferably 8-10 parts, and most preferably about 9 parts.
  • the traditional Chinese medicine composition for the treatment of cardiovascular or cerebrovascular diseases comprises active ingredients composed of the following components 1) and 2):
  • the traditional Chinese medicine composition disclosed herein is preferably provided to patients in the form of processed premix or preparation for direct administration.
  • the component 1) in the composition i.e. “an ethanol extract of 6-12 parts by weight of Rhizoma Chuanxiong and 5-10 parts by weight of Radix Curcumae”, should not be interpreted as requiring Rhizoma Chuanxiong and Radix Curcumae to be extracted together at the same time. Instead, Rhizoma Chuanxiong and Radix Curcumae can be extracted by ethanol separately and then the extracts can be combined, and the combination of the two extracts is equivalent to component 1).
  • the component 2) in the composition i.e.
  • an aqueous extract of 5-10 parts by weight of Radix Cyathulae and the extraction residue of said ethanol extract of Rhizoma Chuanxiong and Radix Curcumae should not be interpreted as requiring Radix Cyathulae and the extraction residue of said ethanol extract of Rhizoma Chuanxiong and Radix Curcumae to be extracted together at the same time.
  • Radix Cyathulae and the extraction residue of said ethanol extract of Rhizoma Chuanxiong and Radix Curcumae can be extracted by water separately and then the extracts can be combined, or Radix Cyathulae, the extraction residue of ethanol extract of Rhizoma Chuanxiong and the extraction residue of ethanol extract of Radix Curcumae can be extracted by water separately and then the extracts can be combined, and the combination of the these extracts is equivalent to component 2).
  • component 1) and “component 2)” in the present disclosure is only for convenience of expression, and does not mean to limit the number of components present in the traditional Chinese medicine composition disclosed herein. It can be understood by those skilled in the art that as long as a composition is substantially equivalent to the combination of the above component 1) and component 2), it falls within the scope of the traditional Chinese medicine composition disclosed herein.
  • the traditional Chinese medicine composition disclosed herein is not limited by a specific preparation method.
  • the traditional Chinese medicine composition is preferably prepared by the following method. Specifically, the preparation method of the traditional Chinese medicine composition comprises the following steps:
  • step (3) combining the concentrates of step (1) and step (2) and then drying.
  • the operation parameters such as the duration of the extraction, the number of times of the extraction, the concentration of the ethanol solution, and the amount of the solvent for each step can be adjusted as needed.
  • the process of step (1) is prepared as follows: weighing 6-12 parts (preferably 8-10 parts) of Rhizoma Chuanxiong and 5-10 parts (preferably 6-8 parts) of Radix Curcumae and combining them, extracting the combination thus obtained with 5 ⁇ -10 ⁇ (e.g. 8 ⁇ ) 50%-70% ethanol (e.g. 55%, 60% or 65% ethanol) for 1-3 times, 1-3 hours each time, filtering the obtained mixture, combining the extraction liquid(s) and concentrating the combined extraction liquid, preferably concentrating to a density of about 1.05-1.15 g/ml.
  • 5 ⁇ -10 ⁇ e.g. 8 ⁇
  • 50%-70% ethanol e.g. 55%, 60% or 65% ethanol
  • the process of step (2) is prepared as follows: weighing 5-10 parts (preferably 6-8 parts) of Radix Cyathulae and mixing it with the extraction residue of step (1), extracting the mixture with 8 ⁇ -15 ⁇ (e.g. 8 ⁇ -10 ⁇ ) with water under reflux for 1-3 times, 1-3 hours each time, filtering the obtained mixture, combining the extraction liquid(s) and concentrating the combined extraction liquid, preferably concentrating to a density of about 1.05-1.15 g/ml.
  • the drying operation of step (3) may be carried out by any drying method commonly used in the pharmaceutical field, such as spray drying, microwave drying, vacuum drying, and the like, preferably by spray drying. If desirable, additives or carriers may be added in the drying process. Usually, a granular or powder solid composition is obtained after drying. The product may be subjected to optional post-processing.
  • the preparation method may comprise additional steps or operations, such as sterilization, heating, cooling or the like, before, after or during the above-mentioned step (1), step (2) and step (3).
  • step (2) In order to prepare the composition comprising the five raw medicines described herein, 5-10 parts of Bulbus Allii Macrostemonis and 6-12 parts of Cortex Eucommiae can be added in the above-mentioned step (2) so as to be extracted together with other medicinal materials; or an independent water extraction step for Bulbus Allii Macrostemonis and Cortex Eucommiae can be inserted between step (2) and step (3); or Bulbus Allii Macrostemonis can be added in step (2), and an independent water extraction step for Cortex Eucommiae can be inserted before step (3).
  • Those skilled in the art can understand that the methods described above are equivalent and can be substituted for each other. Any description of one of the modes mentioned in the specification (including the claims) means that it can be replaced by an equivalent embodiment thereof.
  • the traditional Chinese medicine composition disclosed herein can be made into a preparation according to conventional techniques in pharmaceutical engineering using pharmaceutically acceptable carrier or adjuvant.
  • the active pharmaceutical ingredient in the preparation may be from 0.1 to 99.9% (e.g., 1-99% or 50-98% or 50-95%, etc.), with the balance being a pharmaceutically acceptable carrier or adjuvant.
  • the preparation of the present disclosure can be in any pharmaceutically acceptable dosage form, including: granules, tablets, sugar-coated tablets, film-coated tablets, enteric coated tablets, capsules, oral liquids, dripping pills, dissolving granules, pills, pulvis, suspensions, powders or the like.
  • the preparation of the present disclosure is an oral dosage form such as granules, tablets, capsules, pills or the like.
  • the preparation of the present disclosure is in the form of a unit dosage form, in which a single unit of the formulation is for example a tablet, a pouch of granules, or a capsule.
  • the unit dosage form preferably comprises about 1% to about 90% (e.g., 20-80% or 30-60%) active pharmaceutical ingredient.
  • the unit dosage form for a single administration such as a capsule, a tablet or a sugar-coated pill, may contain about 1 mg to about 100 g (e.g. 10 mg to 80 g, 50 mg to 50 g, 1 g to 20 g, etc.) active pharmaceutical ingredient.
  • the traditional Chinese medicine composition of the present disclosure may be optionally mixed or combined with an inorganic or organic, solid or liquid pharmaceutically acceptable carrier or adjuvant suitable for administration.
  • suitable carriers include, in particular, fillers such as sugars (for example lactose), mannitol or sorbitol, cellulose preparations and/or calcium phosphate (tricalcium phosphate or calcium hydrogen phosphate); binders such as starch paste, gelatin, methyl cellulose and/or polyvinyl vinylpyrrolidone; disintegrants such as starch, carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (for example, sodium alginate).
  • fillers such as sugars (for example lactose), mannitol or sorbitol, cellulose preparations and/or calcium phosphate (tricalcium phosphate or calcium hydrogen phosphate)
  • binders such as starch paste, gelatin, methyl cellulose and/or poly
  • the present disclosure further provides a method of treating a cardiovascular or cerebrovascular disease or condition in a patient in need thereof, the method comprises administering to the patient an effective amount of the traditional Chinese medicine composition according to any one of the embodiments disclosed herein.
  • the patient is preferably a mammal, and more preferably a human being.
  • the administration is preferably oral administration.
  • the present disclosure also provides use of the traditional Chinese medicine composition according to any one of the embodiments disclosed herein for treating a cardiovascular or cerebrovascular disease or condition.
  • the patient is preferably a mammal, and more preferably a human.
  • the present disclosure also provides use of a traditional Chinese medicine composition according to any one of the embodiments disclosed herein for the manufacture of a medicament for the treatment of a cardiovascular or cerebrovascular disease or condition.
  • the disease or condition is preferably a disease or condition in a mammal, especially a human.
  • the medicament is preferably in oral form.
  • the present disclosure also provides a traditional Chinese medicine composition according to any one of the embodiments disclosed herein for use in the treatment of a cardiovascular or cerebrovascular disease or condition.
  • the disease or condition is preferably a disease or condition in a mammal, especially a human.
  • the Traditional Chinese medicine composition is preferably in oral form.
  • the disclosure also provides an oral pharmaceutical preparation or health care product comprising a traditional Chinese medicine composition according to any embodiment and a conventional medicinal adjuvant or auxiliary material.
  • treat used herein are to be construed to refer to prophylactic or preventive treatment, as well as curative or palliative treatment of a disease or condition.
  • cardiovascular or cerebrovascular diseases suitable for treatment with the traditional Chinese medicine composition disclosed herein are coronary heart disease, heart failure (including systolic or diastolic heart failure), angina pectoris, myocardial infarction, thrombosis, stroke, etc.
  • the traditional Chinese medicine composition disclosed herein is suitable for treating and/or preventing myocardial systolic disorder, myocardial diastolic disorder, thrombosis, myocardial ischemia, myocardial hypoxia, or myocardial fatigue, or various cardiovascular and cerebrovascular diseases caused by these diseases, especially myocardial diastolic dysfunction or cardiovascular and cerebrovascular diseases caused by myocardial diastolic dysfunction.
  • DHF diastolic heart failure
  • HFNET normal ejection fraction
  • HFpEF heart failure with preserved ejection fraction
  • SHF cardiac heart failure
  • HFrEF heart failure with reduced ejection fraction
  • the mode and dosage of administration can be determined by a physician according to the specifics of the patient, especially the age, body weight, lifestyle, activity level, severity of disease, etc.
  • a single dose for a mammal is in the range of about 1-20,000 mg/kg, e.g. 2-5,000 mg/kg.
  • a suitable dose may be in the range of 1-2,000 mg/kg, 2-1,000 mg/kg, 5-500 mg/kg or 10-400 mg/kg when administered as a herbal extract premix. If desired, such doses can be divided (optionally evenly) into several portions.
  • the above mentioned doses may be administered at regular intervals, for example, three times a day, once a day, once a week, and the like.
  • mg/kg or “mg ⁇ kg ⁇ 1 ” used in the present disclosure means milligrams per kilogram of the body weight of the mammal (including human) to be treated, and “g/kg” or “g ⁇ kg ⁇ 1 ” means grams per kilogram of the body weight of the mammal (including human) to be treated.
  • Other terms, like “mg/100 g” or “mg/10 g” should be interpreted similarly.
  • FIG. 1A illustrates the effects of different drugs on cardiac systolic function of rhesus monkeys after continuous administration with respect to the change trend of LVEF;
  • FIG. 1B illustrates the effects of different drugs on cardiac systolic function of rhesus monkeys after continuous administration with respect to the change trend of LVEF in each group relative to the baseline value;
  • FIG. 1C illustrates the effects of different drugs on cardiac systolic function of rhesus monkeys after continuous administration with respect to the change trend of FS in each group;
  • FIG. 1D illustrates the effects of different drugs on cardiac systolic function of rhesus monkeys after continuous administration with respect to the change trend of FS in each group relative to the baseline value.
  • FIG. 2A illustrates the effects of different drugs on cardiac diastolic function of rhesus monkeys after continuous administration with respect to the change trend of;
  • FIG. 2B illustrates the effects of different drugs on cardiac diastolic function of rhesus monkeys after continuous administration with respect to the change trend of E/e′ relative to the baseline value;
  • FIG. 2C illustrates the effects of different drugs on cardiac diastolic function of rhesus monkeys after continuous administration with respect to the change trend of e′;
  • FIG. 2D illustrates the effects of different drugs on cardiac diastolic function of rhesus monkeys after continuous administration with respect to the change trend of Vp.
  • the traditional Chinese medicine composition of Example 1 was composed of five raw medicines, i.e. Rhizoma Chuanxiong, Radix Curcumae, Radix Cyathulae, Bulbus Allii Macrostemonis and Cortex Eucommiae.
  • Rhizoma Chuanxiong was collected from Sichuan province, China
  • Radix Curcumae was collected from Guizhou province, China
  • Radix Cyathulae was collected from Sichuan province, China
  • Bulbus Allii Macrostemonis was collected from Jiangsu province, China
  • Cortex Eucommiae was collected from Hebei province, China.
  • Example 1 The process for preparing the traditional Chinese medicine composition of Example 1 was as follows.
  • the filter residue obtained in the previous step was combined with 70 g Radix Cyathulae, 70 g Bulbus Allii Macrostemonis, and 90 g Cortex Eucommiae, the mixture thus obtained was subjected to extraction for 2 hours with 10 ⁇ water and then filtered; then the filter residue was again subjected to extraction for 2 hours with 10 ⁇ water and then filtered; the filtrates obtained in these two extraction processes were combined and concentrated to a density of about 1.1 g/ml, affording a thick paste; and
  • Example 1 the traditional Chinese medicine composition of Example 1 (referred to as “HTL001”).
  • the resulting composition was a brown powder, and it was used directly in the following in vivo and in vitro experiments.
  • the traditional Chinese medicine composition of Example 2 was composed of three raw medicines, i.e. Rhizoma Chuanxiong, Radix Curcumae and Radix Cyathulae.
  • Rhizoma Chuanxiong was collected from Sichuan City, China
  • Radix Curcumae was collected from Guizhou province, China
  • Radix Cyathulae was collected from Sichuan province, China.
  • Example 2 The process for preparing the traditional Chinese medicine composition of Example 2 was as follows.
  • Example 2 the traditional Chinese medicine composition of Example 2 (referred to as “HTL002”).
  • the resulting composition was a brown powder, and it was used directly in the following in vivo and in vitro experiments.
  • Comparative Example 1 Preparation of Comparative Traditional Chinese Medicine Composition 1
  • Comparative Example 2 Preparation of Comparative Traditional Chinese Medicine Composition 2
  • Test substance the composition of Example 2, the composition of Comparative Example 1 and the composition of Comparative Example 2 were dispersed/dissolved into distilled water to the specified concentration, respectively.
  • TTC Triphenyltetrazolium chloride
  • C-5050ZOOM digital camera from Olympus Company.
  • Model control group Compound Danshen Dripping Pills group (146 mg/kg, referred to as CDDP Group)
  • Test group of the composition of Example 2 270 mg/kg, referred to as Group 1
  • Comparative group of the composition of Comparative Example 1 270 mg/kg, referred to as Group 2
  • Comparative group of the composition of Comparative Example 2 270 mg/kg, referred to as Group 3
  • the animals were weighed and anesthetized by intraperitoneal injection of 3% pentobarbital sodium. After fixation, the rats were intubated and ventilated. ECG (electrocardiograph) recording needles (VIN+ for left lower limb, VIN ⁇ for right upper limb, and GND for left upper limb) were inserted to record ECG.
  • ECG electrocardiograph
  • the rats were subjected to thoracotomy at the left inferior axillary margin 3-4 intercostal or 4-5 intercostal and the pleura was torn.
  • the left anterior descending branch of coronary artery was ligated with 3 ⁇ 8 2 ⁇ 6 6/0 suture. The ECG changes were observed and the ischemic indications showed that the model was successful.
  • CDDP group 146 mg/kg
  • Group 1 270 mg/kg
  • Example 2 had protective effect on permanent myocardial ischemia in rats after continuous administration at the dose of 270 mg/kg for 7 days, while the compositions of Comparative Example 1 and Comparative Example 2 did not show obvious anti-myocardial ischemia effect although they were prepared from the raw medicines similar to the composition of Example 2.
  • This result showed that a simple mixture of Rhizoma Chuanxiong, Radix Curcumae and Radix Cyathulae is not therapeutic, that is, the active pharmaceutical ingredients cannot be obtained by conventional alcohol extraction or water extraction.
  • the specific extraction method and extract combination of the present disclosure allow the composition as obtained have significant anti-myocardial ischemia effect.
  • Test substance Chinese medicine composition of example 2 (HTL002), brown powder, dissolved in distilled water to the specified concentration.
  • Compound Danshen Dripping Pills produced by Tianjin Tasly Pharmaceutical Group Co., Ltd., 27 mg/pill, 10 pills a time, 3 times a day.
  • the dosage of Compound Danshen Dropping Pills was calculated to be 105.3 mg/kg for mice by the body surface area method based on human dosage.
  • mice ICR mice, male, 20-22 g, purchased from Peking University Medical Department (Experimental Animal Science Branch).
  • mice After one week of adaptive feeding, the animals were randomly divided into Model group (blank control group), Compound Danshen Dripping Pills groups (25 mg/kg, 50 mg/kg, 100 mg/kg and 200 mg/kg, referred to as CDDP Group), and Test substance groups (150 mg/kg, 300 mg/kg, 600 mg/kg and 1200 mg/kg), with 10 mice in each group. The mice were administered continuously for 15 days, once a day.
  • Model group blank control group
  • Compound Danshen Dripping Pills groups 25 mg/kg, 50 mg/kg, 100 mg/kg and 200 mg/kg, referred to as CDDP Group
  • Test substance groups 150 mg/kg, 300 mg/kg, 600 mg/kg and 1200 mg/kg
  • the animals were put into a 250 ml sealed jar filled with 20 g sodium lime.
  • the jar was sealed with a rubber stopper connected with a burette using silica gel, and the other end of the burette was inserted into water.
  • the rising height of the liquid level in the burette at 0-5 min and 5-10 min, the time of animal death and the rising height of liquid level in the burette at the time of death were recorded respectively.
  • the total oxygen consumption during survival period/20 g, oxygen consumption per unit time/20 g, 0-5 min oxygen consumption/20 g and 5-10 min oxygen consumption/20 g were calculated.
  • normobaric hypoxia Due to incomplete oxidation of acid metabolites and accumulation of CO 2 , normobaric hypoxia can stimulate chemoreceptors or central nervous system, which reflexively leads to deepening of respiration, enhancement of heart beat, increase of cardiac output and redistribution of blood to ensure blood supply to organs.
  • death time i.e. survival period
  • oxygen consumption in survival period of mice were calculated under the condition of normobaric hypoxia.
  • the traditional Chinese medicine composition of Example 2 had different degrees of anti-hypoxia effects on mice at dose of 150 mg/kg, 300 mg/kg, 600 mg/kg and 1200 mg/kg, respectively, for 15 days.
  • Test substance Chinese medicine composition of example 2 (HTL002), brown powder, dissolved in distilled water to the specified concentration.
  • Compound Danshen Dripping Pills produced by Tianjin Tasly Pharmaceutical Group Co., Ltd., 27 mg/pill, 10 pills a time, 3 times a day.
  • the dosage of Compound Danshen Dropping Pills was calculated to be 105.3 mg/kg for mice by the body surface area method based on human dosage.
  • mice ICR mice, male, 20-22 g, purchased from Peking University Medical Department (Experimental Animal Science Branch).
  • mice After one week of adaptive feeding, the animals were randomly divided into Model group (blank control group), Compound Danshen Dripping Pills groups (25 mg/kg, 50 mg/kg, 100 mg/kg and 200 mg/kg, referred to as CDDP Group), and Test substance groups (600 mg/kg and 1200 mg/kg), with 10 mice in each group. The mice were administered continuously for 15 days, once a day.
  • Model group blank control group
  • Compound Danshen Dripping Pills groups 25 mg/kg, 50 mg/kg, 100 mg/kg and 200 mg/kg, referred to as CDDP Group
  • Test substance groups 600 mg/kg and 1200 mg/kg
  • mice with iron wire of 9% body weight on the tail of each animal were put into a bucket with 20 cm depth of water at a temperature of 30° C.
  • the mice were observed to swim to exhaustion (when the mice kept staying under water for 10 seconds and could not float up), and the time was recorded as the weight-bearing swimming time of mice.
  • Sports fatigue is caused by a series of biochemical changes of the body caused by the reduction of muscle contraction force. The most direct manifestation of sports fatigue is the decline of the body's sports endurance. In this experiment, the time of swimming with load can be used as an objective index to judge the physical strength and anti-fatigue ability of mice.
  • Example 2 The traditional Chinese medicine composition of Example 2 could significantly prolong the weight-bearing swimming time of mice and showed anti-fatigue effect at dose of 600 mg/kg and 1200 mg/kg, respectively, for 15 consecutive days.
  • Platelet aggregation rate is a detection index of platelet function. The higher the platelet aggregation rate, the greater the possibility of thrombosis. In arteriosclerosis, coronary heart disease, cerebral infarction, hypertension, diabetes and other thrombotic diseases, platelet aggregation rate is often increased. When the platelet aggregation rate decreases upon treatment, it can not only inhibit thrombosis, but also dissolve the formed thrombus. Therefore, the determination of platelet aggregation rate can be used to observe the curative effect and screen drugs. In this study, thrombin induced rat platelet aggregation model was used to evaluate the inhibitory effect of the traditional Chinese medicine composition on platelet aggregation.
  • Thrombin induced rat platelet aggregation model is a classic model.
  • Thrombin is a serine protease, which is also the main effector protease in the blood coagulation cascade reaction.
  • Thrombin is produced by non-active prothrombin in prothrombin complex through protein cleavage under the action of factor Xa (FXa).
  • Test substance Chinese medicine composition of Example 2 (HTL002), brown powder, dissolved in distilled water to the specified concentration.
  • Positive control drug Plavix (Clopidogrel Hydrogen Sulphate Tablets), from Sanofi (Hangzhou) Pharmaceutical Co., Ltd., 75 mg/tablet, once a day and one tablet per time.
  • the dosage of Plavix was calculated to be 6.75 mg/kg for rats by the body surface area method based on human dosage.
  • Platelet aggregation analyzer model: LBY-NJ4, from Beijing Precil Instrument Co., Ltd.
  • Disposable human venous blood sample collection container from Liuyang Medical Instrument Factory, Hunan province.
  • mice After 5 days of adaptive feeding, the animals were randomly divided into blank control group, positive control group (Plavix group, 6.75 mg/kg) group and test substance group (800 mg/kg), with 20 rats in each group. The animals were administered by gavage for 15 consecutive days, once a day.
  • positive control group Plavix group, 6.75 mg/kg
  • test substance group 800 mg/kg
  • Pentobarbital Sodium was injected intraperitoneally for anesthesia (40 mg/kg).
  • 6 ml blood was collected from abdominal aorta into a disposable human venous blood sample collection container, which was reversed and shaken to mix the sample well.
  • the upper platelet rich plasma (PRP) was aspirated and the number of platelets was counted.
  • the blood having the platelet rich plasma (PRP) removed was centrifuged at 3000 rpm for 10 minutes to obtain the platelet poor plasma (PPP).
  • a small magnetic rod and 300 ⁇ l PRP were added into a square cup, which was preheated for 5 minutes in a constant temperature hole, and 300 ⁇ l PPP was added into another square cup.
  • 5 ⁇ l thrombin (5 U/L) was aspirated with a micro sampler and added to the bottom of each cup. The maximum platelet aggregation rate was measured, wherein 3-4 parallel tests were performed for each blood sample and the average value was taken.
  • the test substance group showed a maximum platelet aggregation rate (40.8 ⁇ 23.5%) which was significantly lower than that of the model group, and the difference was statistically significant (P ⁇ 0.01), suggesting that the test substance had the effect of inhibiting platelet aggregation at the dose of 800 mg/kg (see the table below).
  • test substance could inhibit platelet aggregation upon administration at the dose of 800 mg/kg by gavage for 15 consecutive days.
  • Test substance Chinese medicine composition of Example 2 (HTL002), brown powder, dissolved in distilled water to the specified concentration.
  • Positive control drug Plavix (Clopidogrel Hydrogen Sulphate Tablets), from Sanofi (Hangzhou) Pharmaceutical Co., Ltd., 75 mg/tablet, once a day and one tablet per time.
  • the dosage of Plavix was calculated to be 6.75 mg/kg for rats by the body surface area method based on human dosage.
  • mice After 5 days of adaptive feeding, the animals were randomly divided into blank control group, positive control group (Plavix group, 6.75 mg/kg), and four test substance groups (100, 200, 400 and 800 mg/kg), with 20 rats in each group. The animals were administered by gavage for 15 consecutive days, once a day.
  • positive control group Plavix group, 6.75 mg/kg
  • test substance groups 100, 200, 400 and 800 mg/kg
  • Pentobarbital Sodium was injected intraperitoneally for anesthesia (40 mg/kg).
  • the right common carotid artery and left external jugular vein were separated.
  • a 6 cm long medical surgical suture (No. 0) was placed in the middle of a polyethylene tube, which was filled with normal saline and inserted into the right common carotid artery and the left external jugular vein respectively to form an arteriovenous vascular loop. After 15 minutes, the blood flow was cut off, and the suture was taken out and weighed.
  • the classical rat arteriovenous bypass was used to form the bypass arteriovenous blood flow.
  • the platelets in the arterial blood flow contact the rough surface of the suture, they adhere to the suture, and the platelet aggregation forms platelet thrombosis around the surface of the suture.
  • the weight of thrombosis become smaller. Therefore, the adhesion and aggregation function of platelets can be measured by thrombus weight.
  • test substance could inhibit the formation of arteriovenous bypass thrombosis upon administration at the dose of 800 mg/kg by gavage for 15 consecutive days.
  • HFpEF heart failure with preserved ejection fraction
  • Spontaneous rhesus monkey chronic heart failure model is the world's best clinical model, which is highly similar to human in etiology, pathogenesis, disease progression and other aspects. Therefore, it is the best animal model for studying the pathogenesis of human heart failure, developing early diagnosis and treatment methods, screening and evaluation of new anti-heart failure drugs.
  • This study will evaluate the pharmacodynamics and safety of the composition of Example 2 and EntrestoTM on the systolic and diastolic functions in rhesus monkeys with spontaneous heart failure, and evaluate the efficacy at different doses.
  • the experimental scheme and specific experimental procedure were designed with reference to the following references (and references cited therein):
  • LVEF Left Ventricular Ejection Fraction
  • e′ Peak velocity of mitral annulus motion in early diastolic phase
  • a′ Peak velocity of mitral annulus motion in late diastolic phase
  • Ar-Adur Difference between the duration of pulmonary venous flow reversal and that of mitral blood flow in late diastolic phase
  • Vp Left ventricular flow propagation velocity (velocity of propagation);
  • SBP Systolic blood pressure
  • DBP Diastolic blood pressure
  • the rhesus monkeys were classified based on the measured parameters,
  • SD systolic dysfunction
  • DD diastolic dysfunction
  • the animals were fed with 18% fat diet.
  • the quarantine and preparation period was 4 weeks, and the animals were administered by gavage for 13 weeks.
  • the specific doses were as follows:
  • Entresto group administration of Entresto: 1.66 mg/kg in the first 2 weeks; 3.32 mg/kg in the second 2 weeks; 6.64 mg/kg in the third 2 weeks; and 13.33 mg/kg in the last 7 weeks.
  • Test group administration of HTL002: 130 mg/kg in the first 2 weeks, 200 mg/kg in the following 4 weeks, and 250 mg/kg in the last 7 weeks.
  • Placebo group administration of drug solvent.
  • the animals were observed once a day in cages for skin, hair, eyes, ears, nose, mouth, chest, abdomen, genitourinary department, limbs and other parts, as well as respiratory, exercise, urinary, defecation and behavior changes.
  • the baseline values of LVEF, FS, EDV, ESV, SV, E, e′, a′, S, D, Ar, Ar-ADur, Vp, SBP, DBP, and glomerular filtration rate (GFR) were measured and recorded before administration. The above parameters were measured again at the end of 1, 3, 6, 9 and 13 weeks during administration.
  • FIGS. 1 to 2 The experimental results are shown in FIGS. 1 to 2 .
  • week means the week after the start of administration
  • vehicle refers to placebo group
  • HTL002 refers to test substance group
  • Entresto refers to positive control group
  • baseline refers to the baseline values.
  • FIG. 1 shows the effects of different drugs on cardiac systolic function of rhesus monkeys after continuous administration, where (a) is the change trend of LVEF, (b) is the change trend of LVEF in each group relative to the baseline value, (c) is the change trend of FS in each group, and (D) is the change trend of FS in each group relative to the baseline value.
  • FIG. 1 It can be seen from FIG. 1 that LVEF and FS were improved 1 week after administration of HTL002 and Entresto, and maintained significant enhancement during 3-13 weeks of administration; while there was no significant change in placebo group before and after administration. It can be concluded from FIG. 1 that the systolic function of rhesus monkey can be significantly enhanced after treatment with Entresto or HTL002 for 13 weeks.
  • FIG. 2 shows the effect of different drugs on cardiac diastolic function of rhesus monkeys after continuous administration, where (a) is the change trend of E/e′, (b) is the change trend of E/e′ relative to the baseline value, (c) is the change trend of e′, and (D) is the change trend of Vp.
  • HTL002 significantly improved the diastolic function of rhesus monkeys with spontaneous diastolic dysfunction after 9-13 weeks of treatment, while Entresto did not significantly improve the diastolic function after 13 weeks of treatment.
  • mice 40 ICR mice, half male and half female, aged 28-35 days, provided by Beijing Charles River Experimental Animal Technology Co., Ltd. were used, wherein the body weight of female mice was 15.2-17.5 g, and that of male mice was 15.5-18.3 g.
  • the animals were raised in a PC mouse group rearing box, with cage size of 294*190*125 mm 3 and 5 mice in each box. The animals were allowed to eat and move freely during the whole feeding process. The adaptation period was 6 days.
  • Grouping Methods the animals were weighed before the experiment, and the male and female animals were randomly divided into two groups—administration group (HTL002) and solvent control group, with 20 mice in each group, half male and half female. The experimental animals were fasted for about 4 hours before and 1-2 hours after administration, but were allowed to drink freely. The specific administration scheme is shown in the table below.
  • the maximum dosage method was used in this experiment. 0.5% CMC Na solution provided by China Pharmaceutical Group Chemical Reagent Co., Ltd. was used as the solvent. The concentration of the substance was 0.8 g/ml, and the single dose volume for intragastric administration was 0.4 ml/10 g, totally once. In other words, the dose of the test substance for single gavage was 32 g/kg, which was about 500 times of the proposed human clinical dose.
  • the reaction of the animals to the test substance was observed within 4 hours after the administration, and then observed once a day for 14 consecutive days.
  • MTD maximum tolerated dose
  • the purpose of this experiment is to observe the nature and degree of possible toxic reactions in SD rats caused by repeated intragastric administration of the test substance as well as the development and recovery of the possible toxic reactions.
  • Example 2 The composition of Example 2 (HTL002) was accurately weighed and prepared into suspensions of different concentrations with 0.5% CMC Na solution before administration.
  • the animals were raised in a polypropylene rat group rearing box.
  • the cage size was 545*395*200 mm 3 , with 2-5 animals in each box.
  • the animals were allowed to eat and move freely during the whole feeding process.
  • the adaptation period was 6 days.
  • Methods the animals were weighed before the experiment, and the male and female animals were randomly divided into four groups—solvent control group, low-dose group, medium-dose group and high-dose group, with 30 rats in each group, half male and half female.
  • Administration scheme the administration period was from 1 to 90 days, and the recovery period was from 91 to 121 days.
  • Route of administration intragastric administration.
  • Dosage volume 2 ml/100 g.
  • Frequency of administration once a day.
  • Observation scheme cage side observation was conducted before and after administration, and all animals were observed once a day.
  • the observation contents included the appearance, hair, physical signs, behavior, respiratory state, gland secretion, animal posture, fecal characteristics, death, etc.
  • Administration was continued for 90 days. At the end of administration, 79 animals (1 animal died accidentally) were killed. After 4 weeks of recovery, the remaining 40 animals were killed.
  • the detection indexes included general condition, body weight, feed consumption, blood routine test, serum biochemistry, electrolyte, coagulation index, urine index, gross anatomy and histopathological examination.
  • the content of total cholesterol (CHOL) in the low-, medium- and high-dose groups was higher than that in the solvent control group (16.7%-33.3% increase for female rats and 30.8%-61.5% increase for male rats).
  • the change of CHOL was dose-dependent, suggesting that it might be related to administration, and male rats were more sensitive.
  • the CHOL content returned to the level of the control group.
  • the hematology, electrolyte, coagulation index, urine index and serum biochemical indexes of female and male rats in each administration group were not changed in toxicological significance compared with the solvent control group.
  • Organ weight and organ index at the end of administration, liver weight, liver index, kidney weight and kidney index of the low-, medium- and high-dose groups were higher than those of the solvent control group, and there was a certain dose-dependent effect. At the end of the recovery period, there were no significant changes in organ weight and index between the two groups.
  • Histopathology at the end of administration, compared with the solvent control group, no pathological changes related to administration were found in the organs of the high-dose group. At the end of the recovery period, compared with the solvent control group, there was no cumulative or delayed toxic reaction related to administration in the high-dose group.
  • the results of the above toxicity tests show that the composition of Example 2 was safe for experimental animals when administered at a single dose of about 500 times of the clinical intended dose, and it was still safe for the experimental animals when the long-term continuous administration was about 150 times of the proposed clinical dose, showing that the composition of Example 2 can not only be used as a drug for the treatment of chronic diseases (such as chronic heart failure) for a long time, but also can be used as a health care product for long-term consumption by normal people because it has no obvious side effects and has a preventive effect on thrombosis.
  • chronic diseases such as chronic heart failure
  • This experiment is to verify the efficacy of the composition of Example 1 on the isoproterenol induced cardiac function injury model in rats.
  • Test substance the composition of Example 1 (HTL001), brown powder, soluble in distilled water.
  • Visual Sonics Vevo770 high resolution small animal ultrasound imaging system, with 716 probe.
  • the rats were weighed, and except for the normal control group (10 rats), isoproterenol (27 mg/kg, volume: 0.1 ml/100 g) was injected subcutaneously into the posterior neck for 4 consecutive days, once a day.
  • the surviving animals were divided into model control group, Compound Danshen Dripping Pills group (150 mg/kg, positive control group), HTL001 high-dose group (1800 mg/kg), HTL001 medium-dose group (600 mg/kg) and HTL001 low-dose group (200 mg/kg), with 7 rats in each group. Rats were fasted for 12 hours before the experiment.
  • the cardiac function of the normal control group, model group and each administration group was examined by echocardiography.
  • the animals were anesthetized with gas.
  • the concentration of isoflurane was 3% and the oxygen flow was controlled at 0.6 L/min.
  • the animals were fixed on the examination table in supine position, and the respiratory mask was connected. The anesthesia was maintained with 2% isoflurane and 0.6 L/min oxygen flow.
  • Echocardiographic analysis of the heart the left ventricular short axis section near the sternum was taken and the M-mode ultrasonic motion curve was recorded at the level of mitral chordae tendineae.
  • Example 1 has protective effect on the cardiac function injury induced by isoproterenol at the dose of 600 mg/kg and 1800 mg/kg.
  • Example 1 had similar efficacy and safety with the composition of Example 2, including significant effects on myocardial systolic disorder, myocardial diastolic disorder, platelet aggregation thrombosis, myocardial ischemia, myocardial hypoxia, myocardial fatigue, etc., but the intensity of action was slightly lower in some pharmacodynamic aspects, which could be due to the relative decrease of the concentration of some active ingredients.
  • Example 1 In addition, by administering the composition of Example 1 or Example 2 to some volunteers, it has been proved that the composition of Example 1 and the composition of Example 2 have significant effects on coronary heart disease, angina pectoris, heart failure, thrombosis, etc., and significantly improved the health of patients. In addition, it was also found that the composition of Example 1 had obvious effect in relieving shoulder and back pain symptoms caused by heart disease, which was likely due to the introduction of Bulbus Allii Macrostemonis and Cortex Eucommiae.

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